Sustained peripheral somatosensory stimulations, such as high-frequency repetitive somatosensory stimulation (HF-RSS) and vibrated stimulation, are effective in altering the balance between excitation and inhibition in the somatosensory cortex (S1) and motor cortex (M1). A recent study reported that whole-hand water flow (WF) stimulation induced neural disinhibition in the M1. Based on previous results, we hypothesized that whole-hand WF stimulation would lead to neural disinhibition in the S1 because there is a strong neural connection between M1 and S1 and aimed to examine whether whole-hand WF stimulation would change the neural balance between excitation and inhibition in the S1. Nineteen healthy volunteers were studied by measuring excitation and inhibition in the S1 before and after each of the four 15-min interventions. The excitation and inhibition in the S1 were assessed using somatosensory evoked potentials (SEPs) and paired-pulse inhibition (PPI) induced by single- and paired-pulse stimulations, respectively. The four interventions were as follows: control, whole-hand water immersion, whole-hand WF, and HF-RSS. The results showed no significant changes in SEPs and PPI following any intervention. However, changes in PPI with an interstimulus interval (ISI) of 30 ms were significantly correlated with the baseline value before whole-hand WF. Thus, the present findings indicated that the whole-hand WF stimulation had a greater decreased neural inhibition in participants with higher neural inhibition in the S1 at baseline. Considering previous results on M1, the present results possibly show that S1 has lower plasticity than M1 and that the duration (15 min) of each intervention may not have been enough to alter the balance of excitation and inhibition in the S1. Somatosensory function based on somatosensory information processing in the central nervous system plays a crucial role in our daily lives. Several brain regions are involved in somatosensory function, such as the primary somatosensory cortex (S1), posterior parietal cortex, presupplementary motor area, and basal ganglia . In partSustained peripheral somatosensory stimulation is effective for altering the balance between excitation and inhibition , such asIn vivo experiments identified the anatomic substrate for this cross-systemic plasticity as topographically and functionally specific reciprocal connections between the primary motor cortex (MI) and the primary somatosensory cortex (SI)  stimulation in which sustained somatosensory stimulation by water flow to a large site of the hand is applied; this induces neural disinhibition in the primary motor cortex (M1) . In vivotex (SI) . Other atex (SI) . In humatex (SI) . Additiotex (SI) . Therefotex (SI) , which mThe paired-pulse paradigm has become a standard procedure for evaluating the balance between excitation and inhibition in human participants. It involves the application of pairs of stimuli in close succession (paired-pulse stimulation), which can be used as a marker of intracortical excitability in the S1. In the case of the S1, paired-pulse inhibition (PPI) expresses the result of paired-pulse peripheral stimulations with a short interstimulus interval (ISI), in which the cortical responses to the second stimulus are more significantly suppressed compared to the first stimulus. The PPI is quantified by calculating the ratio of the amplitude of the second response divided by the amplitude of the first response. Small ratios indicate higher PPI, whereas large ratios indicate lower PPI, which is used as a marker for enhanced excitation.The present study aimed to clarify the effect of whole-hand WF on the balance between excitation and inhibition in the S1 using a paired-pulse paradigm. As previous evidence has shown that whole-hand WF produces simultaneous somatosensory stimulation to a large area of the hand , we hypoNineteen healthy right-handed participants  participated in the present study. None of the participants had a history of neurological or psychiatric diseases. All participants signed a written informed consent form, which provided a full explanation of this study and methods before the experimental session. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Niigata University of Health and Welfare (18712-210823).°C ± 1°C, and the water temperature was 33°C ± 1°C. The ambient and water temperatures were modulated to avoid changing the skin temperature. The experimental protocol is shown in The interventions (15 min) were as follows: non-immersed control (CON), whole-hand water immersion (WI), whole-hand WF stimulation (WF), and HF-RSS. In all interventions, the participants were instructed to place their right hand in the sluicing device, keeping it relaxed. The left hand was placed on a soft support beside the body and was kept relaxed. The hands were fixed in the same position for whole-hand WF interventions, using a belt to avoid muscle contractions. For whole-hand WF, WF was applied to the palm of the right hand using a sluicing device  at ∼40 L/min . In all 2 area, with the anode located on the distal phalanx of the right index finger and the cathode located on the proximal phalanx of the same finger. The intensity was set to the maximal intensity tolerated without pain minus 0.1 mA  through the isolator  to surface adhesive electrodes of an approximately 1 cms 0.1 mA .Somatosensory input from peripheral nerves activates several cortical areas, and this modulation can be evaluated using somatosensory evoked potentials (SEPs). We measured SEPs before and after each intervention, according to a previously described methodology . SEPs weSingle-pulse SEP and PPI were measured to assess the balance between cortical excitation and inhibition in the S1. Paired-pulse electrical stimulation of the median nerve was applied with ISIs of 5 ms and 30 ms in combination with SEP recording. The ISIs were determined in two separate sequences based on the methods reported in previous studies , 2017. PThe peak-to-peak amplitudes of the cortical N20 and P25 response components for the first and second paired-pulse stimulations were analyzed. In the paired-pulse trial, the responses after the second response were obtained by subtracting a single SEP . Each PPSingle-pulse SEP amplitudes , latency , PPI ratio , and sensory thresholds were analyzed using statistical software .The distributions of all data were confirmed by the Shapiro–Wilk test. Sensory threshold was entered into a Friedman test with “intervention”  as the within-subject factor. Other parameters were entered into a generalized linear mixed model (GLMM) with “intervention” and “time” (pre and post) as the within-subject factors.p < 0.05. All data are expressed as the mean ± standard deviation.Pearson or Spearman correlation analysis was performed to assess the relationship between PPI at pre-intervention and the change in PPI with each ISI. Statistical significance was set at 2 = 5.654, p = 0.13).For single-pulse SEP, GLMM revealed no significant interactions and main effect in N20, P25, and N20-P25 peak-to-peak, except for the main effect of “intervention” in N20-P25 peak-to-peak .F  = 2.319, p = 0.086, η2p = 0.120; PPI_30 ms: F  = 0.792, p = 0.504, η2p = 0.045]. There was no main effect of “intervention”  and “time” .r = –0.589, p = 0.010).The present data showed that 15-min whole-hand WF, HF-RSS, whole-hand WI, and CON did not affect the balance between excitation and inhibition in the S1, as measured by the N20-P25 amplitude of SEP and PPI. Additional findings revealed that the change in PPI with longer ISI (30 ms) was negatively correlated with the baseline value in whole-hand WF.via N-methyl-D-aspartate receptors located within layers IV/V of SI -expressing inhibitory interneurons inhibit pyramidal cells within the microcolumn through synapses on superficial dendrites . Additio/V of SI . These P/V of SI . The inh/V of SI . PPI at /V of SI . At long/V of SI . TherefoPaired-pulse evoked inhibition has been reported to occur regardless of modality in the motor, visual, auditory, and somatosensory cortices . In the A possible explanation for this is the difference in neural plasticity between S1 and M1. A previous study demonstrated that quadripulse transcranial magnetic stimulation (QPS), which is the most powerful and reliable non-invasive brain stimulation method to induce neural plasticity in humans , was appInterestingly, we found that the higher the PPI_30 ms at pre-intervention, the more the disinhibition after whole-hand WF intervention, but not after other interventions. The results, in which the participants with higher PPI_30 ms at pre-intervention had more disinhibition after whole-hand WF, could be explained by the relationship between the cortical inhibition and neural plasticity. Previous studies have reported that lower cortical inhibition, when assessed by a paired-pulse paradigm, was related to lower neural plasticity in S1 . CorticaThe sensorimotor cortex hyperexcitability represents an important pathogenic mechanism underlying several neurological diseases such as familial adult myoclonic epilepsy type 2 (FAME2) , ALS Ra, dystoniThe present study has several limitations. First, the sample size is small; it was determined on the basis of previous studies, whereas it should have been based on a power analysis. Second, we measured only SEP and PPI to evaluate S1 excitability. To clarify the change in neural balance between excitation and inhibition in the S1 in greater detail, it would be preferable to investigate other biomarkers of inhibitory function such as early and late components of SEP high-frequency oscillation (e- and l-HFO) , which rThe present data showed that 15-min whole-hand WF, HF-RSS, whole-hand WI, and CON did not affect the balance between excitation and inhibition in the S1, as measured by the N20-P25 amplitude of SEP and PPI. Additional findings revealed that the change in PPI with longer ISI (30 ms) was negatively correlated with the baseline value in whole-hand WF. These results indicated that even a 15-min whole-hand WF can induce intracortical disinhibition in the participants with high inhibition in S1, which raises the possibility that whole-hand WF could be a useful tool for improving somatosensory function.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Niigata University of Health and Welfare. The patients/participants provided their written informed consent to participate in this study.DS and KY contributed to conception and design of the study. DC, KI, and DS performed the experiment and statistical analysis. DC and DS wrote the first draft of the manuscript. TF and GO wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.


The aim of this pilot study is to evaluate a Japanese version of brief Cognitive Behavioral Therapy for Insomnia (CBT-I) and contribute to primary care which leads to prevention of a lifestyle-related disease or a psychiatric disorder.A single-arm study in nine patients with chronic insomnia who were under the pharmacotherapy was executed. The Insomnia Severity Index (ISI), the Athens Insomnia Scale (AIS), and the European Quality of Life 5 Items (EQ-5D) were assessed at the beginning of intervention, at the end of intervention, and after 12 weeks.There were no patient dropouts nor adverse events. The average change in ISI score was −7.33 (95% CI: −10.31 to −4.36) at post-treatment and −6.11 (95% CI: −8.20 to −4.03) at the 12-week follow-up point (Cohen’s d = 2.25). The AIS score improved as well, and the EQ-5D score improved after 12 weeks. The safety and efficacy of the brief CBT-I were suggested. The nurse reviewed every session using either audio recordings obtained during each session or notes which were taken if the participant did not permit audio recording.Fundamental information for each patient was collected, including age, sex, the identity of the main disease, complications, the highest level of education completed, and the type and quantity of hypnotic used. The severity of insomnia was set as the primary endpoint of this study. It was assessed using self-report questionnaires of the ISI and the Athens Insomnia Scale (AIS). Secondary endpoint pertaining to quality of life (QOL) was assessed using the European Health-Related Quality of Life. All measurement tools totaled 20 items written in Japanese. Data collection carried out prior to the beginning of brief CBT-I (week 0), at the end of treatment (4 weeks), and at the follow-up point (12 weeks).In addition, in order to suitably evaluate the intervention, the family doctors were requested no change in medication type or dosage.et al., ISI is a measure that reflects the previous 2 weeks and subjectively evaluates the insomnia severity of illness. The ISI measures the nature, severity, and adverse effects of insomnia based on scores from a 7-item questionnaire . The total score (range 0–28) is interpreted as follows: 0–7, no clinically significant insomnia; 8–14, sub-threshold insomnia; 15–21, moderate insomnia; and 22–28, severe insomnia. The Japanese version of the ISI has a high internal consistency (α = 0.84), and its reliability and validity have been verified . The Japanese version has excellent internal consistency , and concurrent validity that the correlation between the AIS and Pittsburgh Sleep Quality Index was significantly high  . The reliability and validity of the Japanese version of the HRQOL have been previously verified .For secondary analysis, the improvement rate at post-treatment and at the 12-week follow-up point was calculated using the respective cut-off points .P < 0.05. All statistical analyses were conducted using SPSS version 23.0 for Windows .In this study, the significance level was set at Characteristic data were obtained from the nine participants. The mean age was 55.0 years  and 66.6% were female. Depression and unidentifiable depression per person existed, respectively. All patients were currently taking some hypnotic drugs.In this clinical trial, there were no patient dropouts nor adverse events. The session time of the brief CBT-I required on average 12.8 min (range = 5–22 min).P = 0.007), and baseline with the 12-week follow-up point . The effect size for change in ISI scores from baseline to the follow-up point (Cohen’s d = 2.25) was high.The average change in ISI score was −7.33 (95% CI: −10.31 to −4.36) at post-treatment and −6.11 (95% CI: −8.20 to −4.03) at the 12-week follow-up point , as well as the baseline with the 12-week follow-up point . The effect size for change in AIS-J scores from baseline to the follow-up point (Cohen’s d = 2.95) was high.The average change in the AIS-J score was −7.22 (95% CI: −9.68 to −4.77) at post-treatment and −6.44 (95% CI: −8.12 to −4.76) at the 12-week follow-up point  but showed significant improvement when comparing baseline with the 12-week follow-up scores . The effect size for change in EQ-5D scores from baseline to the follow-up point (Cohen’s d = 0.99) was large.Figure The improvement rate in the ISI scores calculated at post-treatment was 77.8% (7 subjects) and at the follow-up point was 66.7% (6 subjects). The improvement rate in the AIS-J score calculated at post-treatment was 88.9% (8 subjects) and at follow-up was 77.8% (7 subjects). At the end of the brief CBT-I, one person stopped using the hypnotic and one person decreased the quantity of the hypnotic used. There were no other changes in drug prescriptions.Neither an adverse event nor a dropout was seen by brief CBT-I developed in this research. It is meaningful toward the next research that RCT of Japanese brief CBT-I. If a nurse can perform brief CBT-I widely at the clinic in Japan, it leads to prevention of a lifestyle-related disease or a psychiatric disorder and can expect development of primary care. This is because the brief CBT-I by nurse is expected to make the treatment of sleep more effective through the patient’s own self-care rather than through medication.et al., et al., The improvement rate was also equivalent to the remission rate of standard CBT-I (71%) for medicated insomnia in Japan (Okajima et al., et al., et al., et al., The average time required to administer the brief CBT-I used in this study was 12.8 min. Traditional CBT-I includes all elements in each assessment, such as sleep hygiene, stimulus control therapy, sleep restriction therapy, cognitive therapy, and relaxation (Smith This pilot study was aimed at developing a Japanese version of brief CBT-I, and results suggested the safety and efficacy of this treatment. In order to offer the primary care for insomnia improvement at the medical clinic in Japan, it is necessary to carry out RCT of the brief CBT-I which can be administered by a nurse.


Cyclodextrins (CDs) are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits linked by α-1,4 glycosidic bonds. The shape of CD molecules is similar to a truncated cone with a hydrophobic inner cavity and a hydrophilic surface, which allows the formation of inclusion complexes with various molecules. This review article summarises over 200 reports published by the end of 2021 that discuss the complexation of CDs with antibiotics and antibacterial agents, including beta-lactams, tetracyclines, quinolones, macrolides, aminoglycosides, glycopeptides, polypeptides, nitroimidazoles, and oxazolidinones. The review focuses on drug-delivery applications such as improving solubility, modifying the drug-release profile, slowing down the degradation of the drug, improving biological membrane permeability, and enhancing antimicrobial activity. In addition to simple drug/CD combinations, ternary systems with additional auxiliary substances have been described, as well as more sophisticated drug-delivery systems including nanosponges, nanofibres, nanoparticles, microparticles, liposomes, hydrogels, and macromolecules. Depending on the desired properties of the drug product, an accelerated or prolonged dissolution profile can be achieved when combining CD with antibiotics or antimicrobial agents. Due to the high costs associated with the development of innovative drugs, a very long time to introduce them to the market, and a huge risk of failure in clinical trials, more and more work is focused on the development of new drug-delivery systems  based onCDs are a valuable subject of research in many areas, including pharmacy , food chNative CDs consist of 6, 7, or 8 glucopyranose units, referred to as α, β, and γ, forming a macrocyclic ring. One of their most important properties is that their shape is similar to a truncated cone, with a hydrophobic inner cavity and hydrophilic surface. This enables them to form inclusion complexes (ICs) with different molecules using non-covalent interactions, such as the host–guest interaction and hydrogen bonding. Many derivatives of CDs have been synthesised but only three  are frequently used as excipients due to their proven non-toxicity . DependiOur review focuses on drug-delivery applications such as improving solubility, modifying the drug-release profile, slowing down the degradation of the active substance, improving biological membrane permeability, enhancing antimicrobial activity, and masking the bitter taste. Works that only deal with the structures of the complexes are also included, as knowledge of the structure can aid in understanding macroscopic properties at the molecular level. Some antibiotic molecules are too large to be included in the CD cavity; however, due to the improvement of pharmaceutical properties, they are also presented in this article. On the other hand, our study omits reports in which CDs were used as constituents of a pharmaceutical formulation but their influence on the system’s properties was not investigated.The particular interest in CDs in the field of pharmaceutical applications results from their ability to modulate several properties that influence the action and therapeutic profiles of drugs. The main purpose of utilising CDs and their derivatives as drug carriers is to increase the solubility of drugs belonging to Class 2  or Class 4  of the Biopharmaceuticals Classification System (BCS) , ultimatIn some cases, the complexation of a drug with a CD can also increase the permeability through biological membranes and the effects of the type and concentration of the CD on the interactions with different types of cell membranes and biological barriers have been extensively described . Given tFormulations based solely on CDs do not have any intrinsic mechanism to control the release of the drug (most such systems are immediate-release dosage forms); therefore, smart nanosystems have been created in combination with various nanomaterials to control the drug release. These systems are very frequently designed to release at a specific site, through the use of internal  and external  stimuli, which have been discussed in detail in the reviews of Haimhoffer et al.  and RealThe release of API from the polymeric delivery systems can be governed by diffusion or the processes of swelling or relaxation of the polymeric chain . To deteall rate .Moreover, despite the many advantages of CDs, there is one disadvantage that limits their use in solid dosage forms, which relates to large amounts of CDs that are required to solubilise a drug, thus increasing the formulation bulk. To overcome this obstacle, multicomponent complexes have been developed.®®®, and carboxymethyl cellulose (CMC). Other multicomponent complexes with organic acids such as citric, gluconic, tartaric, lactic, and malic acids, or with organic bases such as three mono-, di-, and tri-ethanolamines or amino acids , have already been described [Ternary complexes with the addition of auxiliary substances such as (i) amino acids, (ii) organic acids and bases, and (iii) water-soluble polymers have been extensively explored to increase complexation efficiency, and to stabilise or prevent aggregation of the complexes . The watescribed . The useescribed .Another modern approach in the use of CDs is the development of CD-modified nanomaterials for drug delivery. Systems consisting of CDs, drugs, and lipid-based polymerics or surface-modified nanocarriers have been described by Real et al. . RecentlN,N′-methylenebisacrylamide). The basic concepts of hydrogels, in terms of their synthesis, properties, and applications, have been extensively described in an excellent review by Bashir et al. [Hydrogels are another approach . The user et al. . Neverthr et al. .Antibiotics are very diverse in terms of their antibacterial activity, physicochemical properties, polarity, target point, side effects, and chemical stability. For example, fluoroquinolones and tetracyclines suffer from photodegradation, whereas beta-lactams and tetracyclines are unstable in aqueous solution. It is therefore particularly important to stabilise such sensitive drugs, especially when administered parenterally . There aAntimicrobial activity is expressed as a function of time or concentration . Antibiop < −0.1) may interact with the bacterial cell membrane’s anionic surface but cannot penetrate into the lipid bilayer membrane’s apolar hydrocarbon core, while relatively hydrophobic CDs (log p > 0.1) may disturb the surface interaction. The authors concluded that only balanced derivatives can disrupt the bacterial membrane [Due to the growing drug resistance among bacteria, it is very important to increase antimicrobial efficacy, which can occur through the spontaneous formation of hydrogen bonds between CDs and several components of the bacterial cell membrane . Hence, membrane . The stuBeta-lactam antibiotics include numerous compounds characterised by the presence of a beta-lactam ring in the molecule, which is responsible for the antibacterial activity. This group includes penicillins, cephalosporins, carbapenems, and monobactams, as well as beta-lactamase inhibitors . The phyPenicillins, historically the first antibiotics to be discovered, contain a so-called penam moiety, i.e., fused beta-lactam and thiazolidone rings . Some peDetailed information on the types of CDs used, the methods of complex preparation, and the techniques used to characterise the obtained products in each indicated article are summarised in Benzylpenicillin (BP) (known as penicillin G) undergoes hydrolysis of the beta-lactam ring in aqueous solution and has a short biological half-life as well as low oral bioavailability, which makes its use difficult. Therefore, the main goal of complexation with CDs is to prevent its degradation. Pop et al. [p et al.  improvedp et al. , who invp et al.  extendedp et al. . Aki et p et al.  investigPopielec et al.  investigPhenoxymethylpenicillin (PMP)  was combined with β-CD by a saturated aqueous solution method to mask the unpleasant smell of this pharmaceutical raw material [material .Ampicillin is one of the best-studied beta-lactam antibiotics with regard to the formation of CD complexes, due to its low bioavailability. Like BP, ampicillin is hydrolysed in aqueous solution to form polymers with strong antigenic properties. Meanwhile, many bacterial strains produce beta-lactamases, i.e., enzymes that hydrolyse the beta-lactam ring, causing its inactivation and the formation of degradation products. Accordingly, the formation of an IC with CD can directly limit the development of bacterial drug resistance by inhibiting the degradation of ampicillin. The inhibitory effect of β-CD on ampicillin polymerisation in aqueous solutions was found by fast-atom bombardment mass spectrometry (MS) and circular dichroism spectroscopy [N-acetylglucosamine. These monosaccharides are recognised by bacterial lectins, i.e., carbohydrate-binding proteins which are highly specific for sugar groups, and the resulting complexes therefore interacted more strongly with lectins immobilised on the surface.troscopy , whereastroscopy . Aki et troscopy  investigtroscopy  conductetroscopy  conductetroscopy  synthesitroscopy  suggestePivampicillin, a prodrug of ampicillin, was one of the three test beta-lactam antibiotics (in addition to cefuroxime axetil and cefetamet pivoxil) selected by Mizera et al. [a et al.  to develAmoxicillin complexes with CDs have been studied by many research groups, mainly to propose a delivery system that will help stabilise amoxicillin in an acidic environment and support the more effective use of amoxicillin to eradicate Helicobacter pylori in the treatment of gastric and duodenal ulcers. NMR spectroscopy confirmed the complexation of amoxicillin with β-CD and γ-CD, while α-CD only had a very small effect on the chemical shifts of amoxicillin [xicillin . Aki et xicillin  investigxicillin . As β-CDdicloxacillin complexes with α-, β-, γ-, and HP-β-CD were also studied at different pH levels [cloxacillin sodium into β-CD, the complex was examined in solution by NMR and fluorescence and then obtained in the solid state by the co-precipitation method [Methicillin in combination with a specially designed β-CD derivative, namely per-6-(4-methoxylbenzyl)-amino-6-deoxy-β-CD HCl salt, showed an increased affinity for a resistant target such as altered penicillin-binding protein (PBP) 2a, which resulted in the recovery and enhancement of its antibacterial activity against methicillin-resistant strains of Staphylococcusaureus (MRSA) [Oxacillin, which is anionic at physiological pH, was combined with specially designed cationic CD derivatives [Solubilisation and stabilisation of H levels . The IC n method . The ress (MRSA) . Since tivatives . IsotherCephalosporins constitute a subgroup of beta-lactam antibiotics in which the beta-lactam ring is fused with a dihydrothiazine ring, thereby forming a so-called cephem moiety . This lacefalexin  binding mechanism to the β-CD cavity, structural characterisation was performed by NMR, molecular mechanics, quantum mechanical calculations, and molecular docking [To understand the basic aspects of the  docking .Cefuroxime axetil  is a prodrug of cefuroxime that belongs to BCS Class II with a bioavailability of 37% after oral administration on an empty stomach [ stomach . Cefurox stomach . Mizera  stomach  obtained stomach . Indeed,®®® 200. The ternary systems performed better than the binary systems due to the synergistic effect of ternary complexation and the particle size reduction achieved by the spray-drying technology. The stability constant for the combination of HP-β-CD/cefuroxime axetil with or without the addition of polymer can be set in the following order: PEG 4000 > poloxamer 188 > HPMC > PVP K-30 > binary system. A similar attempt to include cefuroxime axetil in β-CD with and without L-arginine showed that the ternary system performed better than the binary system, offering much better solubility and dissolution rate than cefuroxime axetil alone [Another study showed the affinity order of four CDs for cefuroxime axetils as follows: HP-β-CD ~ γ-CD > β-CD ~ α-CD . Raman sil alone . The teril alone .cefaclor with β-CD were prepared and their stability was compared to a parent drug by means of the thin-layer chromatographic (TLC) densitometric method, using such parameters as the rate constant and activation energy [Complexes of n energy . β-CD shCeftazidime  was included into HP-γ-CD by the freeze-drying method [g method . In anotg method . Better Cefixime (BCS class IV) was combined with Captisol®®®, which is a patent-protected variation of SBE-β-CD whose chemical structure is designed to enable the creation of new products by significantly improving the solubility, stability, and bioavailability. The addition of hypromellose had a stabilising effect on the cefixime-Captisol®®® complexation, reducing the degradation rate by approximately 1.5 times (in the range of 303–353 K), while povidone K-30 and macrogol (PEG) 4000 had an unfavourable effect due to steric hindrance, preventing the guest from entering the CD cavity [S. aureus and E. coli than cefixime alone.D cavity . PamudjiD cavity  applied D cavity . Both weD cavity . AnotherD cavity . These sw/v, HPMC K4 at 0.1% w/v) significantly improved the drug solubility and dissolution rate, due to the increased efficiency of CD complexation. The increase in the dissolution rate was found to be higher for the ternary systems than for the corresponding binary compositions, and the ternary systems with HPMC were found to exhibit a faster dissolution profile compared to other systems. The apparent stability constants of cefixime with binary and ternary systems were ranked as follows: cefixime-β-CD-HPMC > cefixime-β-CD-PVP > cefixime-β-CD. Similarly, a synergistic effect of L-arginine in combination with cefixime and β-CD or HP-β-CD resulted in the ternary system being most effective, resulting in a tremendous improvement in physicochemical properties (which was better for the HP-β-CD) compared to the pure drug [A different approach to improve the solubility and dissolution rate of cefixime was the preparation of binary and ternary systems by the freeze-drying method . The resure drug . In addiure drug  investigCefetamet pivoxil was analysed as one of three model beta-lactam antibiotics to develop a machine learning algorithm [lgorithm . The mosCefpodoxime proxetil (CPP) (BCS Class II/IV) was complexed with β-CD in a 1:2 molar ratio. The freeze-dried product exhibited the highest dissolution rate at almost 90% after 30 min compared to 34% and 42% for the physical mixture and solvent evaporation, respectively [Neisseriagonorrhoeae strains showed an enhanced therapeutic efficacy of the prepared freeze-dried complexes. Recently, a spray-drying technique was proposed instead of kneading to obtain CPP complexes with β-CD, HP-β-CD, and M-β-CD with a better release profile and enhanced antibacterial activity [E. coli and Klebsiella pneumoniae of binary systems were found to be two to four times lower than that of CPP. Meanwhile, the MIC values for S. aureus of the complexes with HP-β-CD and M-β-CD were two times lower than that of pure API, while the complex with β-CD displayed the same MIC value as the pure CPP.ectively . In vitractivity . The solAnother study proposed the complexation of CPP with HP-β-CD with the addition of a soluble polymer, sodium CMC, to form a ternary system ,88. Not Cefdinir  was kneaded with β-CD and HP-β-CD in a 1:1 molar ratio, showing that β-CD had a greater effect on solubility enhancement (101% for β-CD versus 23% for HP-β-CD), while HP-β-CD allowed for better antimicrobial activity [7-β-CD. The MIC results against S. aureus and E. coli showed that the formation of ICs, especially with HP-β-CD, enhanced the antimicrobial activity of the drug, which is consistent with the results [activity . In otheactivity  and HP-βactivity  complexeactivity . Recentlactivity  showed i results . SubsequThe following description of three carbapenem antibiotics is accompanied by Meropenem is characterised by good solubility in water, but also high instability in aqueous solutions due to the hydrolysis of the amide bond in the beta-lactam ring and intermolecular aminolysis resulting in a dimeric product.Pseudomonas aeruginosa, Rhodococcus equi, and Listeria ivanovii [Inclusion of meropenem in the β-CD cavity only slightly increased its solubility (by approximately 15%) . Howeverivanovii .Ertapanem is unstable at room and refrigerated temperatures and is thus prone to degradation with the formation of dimer and open-ring degradation products. To overcome these drawbacks, HP-β-CD was used as an additive in a lyophilised formulation, acting both as a cryoprotective and a stabilising agent [ng agent .Tebipenem pivoxil is the first oral antibiotic in the class of carbapenems. It was complexed with β-CD in a 1:1 molar ratio by the dry mixing method, and characterised by spectroscopic (Fourier-transform infrared spectroscopy (FT-IR) and Raman) and thermal ) methods [S. aureus, P. aeruginosa, Enterococcus faecalis, and Proteusmirabilis were increased, but permeability through the Caco-2 cell monolayers was decreased. methods . As a reTetracyclines are antibiotics with a very similar structure, theoretically with a wide range of antibacterial activity. Currently, they are significantly limited due to the growing bacterial resistance to antibiotics from this group. Doxycycline is characterised by higher lipophilicity compared to tetracycline, and consequently is better absorbed from the gastrointestinal tract and achieves a higher concentration in many tissues . For detdoxycycline/HP-β-CD complexes is increased efficacy against bacterial biofilms, which shows promise in the treatment of aggressive and unresponsive forms of periodontitis [Aggregatibacter actinomycetemcomitans suspension and biofilms 8–16-fold and improved the bactericidal efficacy in comparison with free doxycycline and HP-β-CD complexes at different stoichiometric ratios . In another study, focusing on the adhesion of β-CD to the S. aureus cell membrane through hydrogen bonding, a synergistic effect was obtained with the ionic interactions that may arise between the cationic drug and the anionic cell surface, which in turn was responsible for the higher activity of doxycycline/β-CD complex against S. aureus compared to pure doxycycline [S. aureus revealed a 135-fold decrease in MIC and an 8-fold decrease in minimal bacterial concentration (MBC). Kogawa et al. [An advantage of dontitis . The doxycycline . An in va et al.  observed22H24N2O8·HCl·½ H2O·½ C2H5OH) with different CDs [On the other hand, complexes of doxycycline hyclate  and density functional theory (DFT) [For ry (DFT) . A qualiTigecycline was described in a patent WO 2017/118994, where SBE-β-CD was used as a stabilising agent for a freeze-dried pharmaceutical composition for parenteral administration [stration .The experimental conditions and selected results of the cited reports are summarised in Chloramphenicol (phenicol  was intr−8 M) and has several polymorphic forms  [Chloramphenicol is only used in the cases of severe, life-threatening conditions where there is no alternative to its use. In many countries, chloramphenicol has been withdrawn from systemic preparations and remained in topical formulations only. Chloramphenicol is a lipophilic antibiotic, well-absorbed from the gastrointestinal tract, with a bioavailability of 90–100%, but with poor water solubility due to the presence of the nitrobenzene moiety, and is characterised with a bitter taste. As a result, hydrophilic prodrugs  are generally used for the preparation of pharmaceutical compositions. The inclusion into the cavity of the CD molecule can reduce the toxicological properties of chloramphenicol . Chloramastable) . In the astable) .Ali et al.  conducte−1 for M-β-CD versus 86.3 M−1 for HP-β-CD). Shi et al. [O-methyl)-β-CD (Dimeb) increased 2.2-fold, and is greater than in the presence of β-CD, HP-β-CD, and M-β-CD, similar to the complex stability constant. The results obtained by spectroscopic methods showed that the nitrophenyl moiety of chloramphenicol was deeply inserted into the cavity of Dimeb from the narrow rim of Dimeb, which differs from the complex with β-CD.Li et al.  applied i et al.  showed tO-methyl-β-CD (Trimeb) [E. faecalis strains and a remarkable ten-fold MIC reduction against Listeria monocytogenes.Three different procedures were applied to prepare ICs of chloramphenicol in the solid state: (i) co-crystallisation with β-CD from aqueous solution, (ii) the solvent-free co-grinding with β-CD, and (iii) co-dissolution in ethanol with heptakis-2,3,6-tris-(Trimeb) . The co-S. aureus, E. coli, and P. aeruginosa when tested by agar diffusion methods [N-acetylcysteine (NAC), β-CD [Staphylococcus spp., as assessed by the crystal violet and XTT assays. The complexation also resulted in the reduced leukocyte toxicity. One way to induce the resistance to antibiotics is through the formation of a bacterial biofilm [S. aureus and a 1.3-fold decrease in the case of MRSA.Aiassa et al.  improved methods . FurtherC), β-CD , and γ-CC), β-CD  were preC), β-CD  decrease biofilm . In this biofilm . The solFlorfenicol (FF) is approved for veterinary use only. Fan et al. [n et al.  conducten et al.  describeThis section discusses the CD complexes of the next generations of quinolone antibacterial agents: the “old” quinolones (first generation) and fluoroquinolones (second–fourth generations). The experimental details are summarised in First-generation quinolones were introduced for the treatment of urinary tract infections. Attempts to use them in other infections have failed because these compounds are unlikely to generate adequate concentrations in body fluids other than urine . The sidnalidixic acid into α- and β-CD cavities using UV-VIS spectroscopy and electrochemical methods such as differential pulse stripping voltammetry and cyclic voltammetry. The logarithms of the binding constants were calculated from voltammetric data, indicating that nalidixic acid was bound more strongly to β-CD, with a more apolar cavity, than to α-CD. A combination of the experimental results and molecular modelling studies allowed the structure of the complexes to be proposed, with the 2-methylpyridine group inside the CD cavity and the carboxyl group of the drug remaining outside the β-CD cavity, forming an additional hydrogen bond with the OH group of β-CD. In another study, β-CD/nalidixic acid solid dispersions were prepared, thus achieving an enhanced dissolution rate for these systems compared to solid dispersions with PVP (obtained by solvent evaporation) or sodium starch glycolate (SSG) [Shehatta et al.  studied te (SSG) . The relte (SSG)  used UV-pipemidic acid (1:1) in the solid state [E. coli and S. aureus was higher than that of the pure drug. Furthermore, tests on human hepatoblastoma HepG2 and MCF-7 cell lines using the MTT assay revealed that the complex exhibited a higher antitumor activity than sole pipemidic acid.A kneading method was used to prepare β-CD complexes with id state . The resOxolinic acid was studied in combination with HP-β-CD to improve the photostability of this drug [his drug , demonstAttaching a fluorine atom in the C6 position of the 1,4-dihydroquinoline ring  results Ofloxacin is characterised by photochemical instability, and hence many articles are concerned with improving drug stability when complexed with CDs. In fact, CD can cover some parts of ofloxacin, which show light sensitivity and are degraded by contact with light, thereby significantly reducing the degradation rate. Koester et al. [N-methylpiperazinyl moiety in the CD cavity, which was confirmed by NMR studies. The piperazinyl ring is probably one of the groups responsible for ofloxacin photodegradation.r et al.  demonstrE.coli and S. aureus, and at the same time as antitumor agents, similar to pipemidic acid [Different forms of ofloxacin are known to exist as a function of pH, namely protonated (predominant in acidic media), anionic , and neutral species. Some studies have suggested that CDs have a different inclusive capacity to different forms of ofloxacin in solutions of different pH levels, namely β-CD is most suitable for the inclusion of the neutral form and HP-β-CD is suitable for the acidic form . The biodic acid .The fluorescence decay curves of ofloxacin, ciprofloxacin, and sparfloxacin with and without CD allowed the lifetimes to be arranged in the following order: ofloxacin/β-CD > ofloxacin/α-CD > ofloxacin > sparfloxacin/β-CD > sparfloxacin/α-CD > sparfloxacin > ciprofloxacin/β-CD > ciprofloxacin/α-CD > ciprofloxacin . The oflThe formation of a complex of M-β-CD with ofloxacin in a 1:1 molar ratio was confirmed by UV-VIS, FT-IR, fluorescence spectroscopy , and theCiprofloxacin is one of the best-studied antibacterial drugs in terms of inclusion complexation with CDs. In most cases, the combination of ciprofloxacin with CD is part of a modern form of drug-delivery system, such as a hydrogel, nanofibres, or NPs  was obtained by the solvent evaporation method to obtain fast-dissolving tablets to increase patient compliance, increase solubility, and mask the bitter taste [An IC of er taste . The preRufloxacin was used in combination with CDs and HPMC in the formulation of ophthalmic solutions [w/v) HPMC to solutions containing rufloxacin/HP-β-CD complexes increased the solubilising effect of this CD, thus reducing the amount of CD necessary for solubilisation of 0.3% (w/v) rufloxacin. Preliminary pharmacokinetic data in rabbits indicated that the ocular bioavailability of 0.3% (w/v) rufloxacin solubilised by HP-β-CD was higher than the 0.3% (w/v) rufloxacin suspension used as a reference.olutions . The addNorfloxacin is another extensively studied fluoroquinolone drug. Guyot et al. prepared complexes with β-CD and HP-β-CD by the freeze-drying method, which significantly improved the solubility and dissolution rate of the drug [the drug . In anotthe drug . The disMendes et al. ,180 analI (B hydrate) [I form had the most potent activity. This polymorph was found to be the best candidate for the preparation of alternative matrices using β-CD to enhance the biopharmaceutical properties.Several articles describe the complexes of individual polymorphs of norfloxacin with β-CD, obtained by the kneading and freeze-drying methods ,173,174.1H NMR chemical shifts were shown to be an additional procedure to adequately predict the way in which the norfloxacin molecule is incorporated into β-CD. Another study suggested that the main factors affecting molecular recognition were the size match between M-β-CD and the guest, as well as the hydrophobic properties of the guest molecule [Maia et al.  performemolecule . The obtw/w) of the hydrophilic polymer HPMC improved the solubility of the norfloxacin/β-CD complex (1:1), but a further addition above 5% (w/w) reduced the solubility of norfloxacin [Bacillus subtilis, S. aureus, and E. coli also showed better antimicrobial activity as compared to the pure drug. Other ternary complexes of norfloxacin with HP-β-CD were prepared, using glutamic acid, proline, or lysine as the third component [The ternary system showed that the addition of up to 5%  is rarely prescribed due to a high incidence of phototoxicity [toxicity . Mourya toxicity  determintoxicity . Chao ettoxicity  preparedTosufloxacin tosylate was complexed to HP-β-CD by three different methods. The solvent evaporation technique allowed for a 42-fold increase in water solubility, and improved the stability and dissolution of the drug [2 utilises the special properties of the supercritical fluid to combine the solubility of the liquid and the diffusion ability of the gas, thereby controlling the speed of supersaturation and consequently the particle size as well as the morphology of the product [E. coli and S. aureus.the drug . In the the drug . In phos product . Resultsmoxifloxacin (the fourth generation of fluoroquinolones) with β-CD in 1:1 stoichiometry was prepared using the freeze-drying method, and the thermodynamic parameters  associated with the inclusion process were determined [1H NMR titrations revealed that the stabilities of the ICs were pH-dependent. The most stable complex was obtained at the pH at which moxifloxacin is present as a neutral molecule (beside monocationic and monoanionic), with the tricyclic moiety entering the host cavity. Studies have shown that supramolecular interactions do not significantly affect the antibacterial activity of the drug. The highest increase of antibacterial activity was found against E. faecalis. Kudryashova’s research group published a series of articles on the complexation of moxifloxacin with β-CD derivatives or their oligomers [A complex of termined . Szabó etermined  continueligomers ,205,206.ligomers . The folligomers . HoweverMacrolide antibiotics consist of a large, usually 14-, 15-, or 16-membered lactone ring combined with sugar molecules, one of which possesses a dimethylamine moiety. The systematic summary of the experimental details of the cited reports is presented in erythromycin base is sparingly soluble in water and poorly absorbed from the gastrointestinal tract. Moreover, it is unstable, especially in the acidic environment of the stomach, where it undergoes spontaneous cyclisation. Some salts or esters of erythromycin, such as stearate, acistrate, ethyl succinate, propionyl erythromycin lauryl sulphate (estolate), glucoheptonate, and lactobionate, are more stable in acidic environments [The ronments . Erythroronments . In otheIn contrast to the above-mentioned results, three ICs of erythromycin with β-CD were formed by kneading, co-precipitation, and freeze-drying at a molar ratio of 1:1 ,214. TheClarithromycin is a semi-synthetic 14-member macrolide, poorly water-soluble (<0.1 mg/mL). Structurally, it differs from erythromycin only in the substitution of the O-methyl group for the hydroxyl group in the lactone ring. Salem et al. [Mycobacterium avium in human peripheral blood monocyte-derived macrophages was slightly lower than that of the free drug, possibly due to the high stability of the IC. In a different approach, the solid-state ternary complexes of clarithromycin with β-CD and citric acid (1:1:1) were prepared by co-evaporation and lyophilisation [w/w of the drug content and 30% ethanol as a solvent showed more than 80% of drug release at the end of one hour [m et al.  increaselisation ,219 or wlisation . The obtone hour .Another ternary system, consisting of clarithromycin, HP-β-CD, and PVP K30, was prepared using two methods , showingSpiramycin consists of a 16-membered lactone ring with 2 amino sugars and 1 neutral sugar. Spiramycin was found to form a non-host–guest complex with M-β-CD in the stoichiometric ratio of 1:3, but not with the native α- or β-CD [w/v) of M-β-CD to the culture medium showed a high stimulating effect on the production of spiramycin by Streptomyces ambofaciens, while α- or β-CD poorly increased the antibiotic yields. or β-CD . The resAzithromycin suffers from extensive hydrolytic loss of the cladinose sugar moiety at pH < 6.0, leading to a microbiologically inactive metabolite. The opening of the lactone ring has also been noticed in the pH range of 6.0–7.2. Saita et al. [w/w) on azithromycin dihydrate solubility was investigated [a et al.  investigstigated . DependiThis section combines and discusses antibacterial drugs belonging to the groups of aminoglycosides, glycopeptides, polypeptides, nitroimidazoles, oxazolidinones, as well as three other compounds , because only a few reports about CD complexation for each group can be found. a value above 8, so they are largely dissociated in all body fluids, which is important for their behaviour in the body. Several modern delivery systems were designed for these antibiotics, discussed in detail in Aminoglycosides  are largGlycopeptides are large-molecule antibiotics composed of a peptide ring linked to two sugar molecules . Two glyvancomycin to interact with three hydrophobic CDs  and the influence of the preparation technique on the prolongation of the drug delivery for site-specific treatment of bone infections were investigated [The ability of stigated . It has stigated . The in stigated  supplemeTeicoplanin, like vancomycin, has been combined with triacetyl-α-, -β-, or -γ-CD to prolong the release of this hydrophilic drug [lic drug . TriacetPolymyxin B is an amphiphilic polypeptide antibiotic, as it consists of a ring of amino acids linked by peptide bonds and an additional peptide chain with a different amino acids sequence. Polymyxins exhibit considerable toxicity. This group includes five antibiotics, polymyxins A–E. Two compounds are on the market: polymyxin B, which is applied topically, and polymyxin E, known as colistin [colistin . Angelovcolistin  used theMetronidazole benzoate in combination with β-CD was first studied in 1984 by Andersen and Bundgaard [Trichomonas vaginalis. Chadha et al. [undgaard . In addiundgaard . Malli eundgaard  used twoa et al.  investigtinidazole/β-CD complexes [Microwave energy was utilised to prepare solvent-free solid dispersions containing omplexes . The micOxazolidinones  are a nolinezolid/β-CD complex was investigated with respect to the drug/β-CD binding to bovine serum albumin (BSA) by means of the measurement of the fluorescence quenching and Förster resonance energy transfer to understand the pharmacokinetics of the drug in β-CD encapsulated form [2 M−1. NMR studies showed that the amide substituent on the oxazolidinone ring of linezolid was involved in its binding to β-CD. Meanwhile, the encapsulation of linezolid by β-CD decreased the strength of binding of the linezolid to BSA by blocking the hydrogen bonding and hydrophobic interaction of the linezolid. Mohapatra et al. [w/v) on the increase in solubility and masking the taste of linezolid in the multi-component β-CD IC. The complexes were obtained by different methods with or without HPMC, and the microwave irradiation allowed for obtaining the best results. The drug content, solubility, and dissolution of linezolid in ternary complexes were significantly higher than those of the binary complex.The ted form . The stoa et al.  investigTedizolid has very low solubility in water, and therefore its prodrugs such as tedizolid phosphate (TED-PO4) and tedizolid phosphate sodium salt were developed. Bednarek et al. [O-acetyl-6-sulfo)-β-CD. Stoichiometry of the complexes was determined using the Job plot only for TED-PO4, showing a 1:2 ratio in the case of γ-CD and predomination of a 1:1 complex with β-CD. T-ROESY spectra allowed to conclude that parent tedizolid penetrates deeper into β-CD and γ-CD cavities than TED-PO4. Paczkowska-Walendowska et al. [−6 cm/s using the PAMPA system) and high microbiological activity expressed by a decrease in the MIC value in the case of E. faecalis and E. faecium.k et al.  performea et al.  preparedFusidic acid in the form of a sodium salt formed 1:1 complexes with γ-CD and 1:2 complexes with β-CD, and the structures of the obtained complexes were proposed [S. aureus to pure fusidic acid.proposed . Marian proposed  used thrFurazolidone belongs to the class of nitrofuran derivatives. Carvalho et al. [Leishmania amazonensis. In another report, the scope of the study was extended to the use of HP-β-CD, and the formation of more effective interactions was observed for a complex prepared by lyophilisation in a 1:2 molar ratio than in a 1:1 ratio or using the kneading method [o et al.  preparedg method .ceftazidime and accelerated the drug-release profiles without any significant changes in the release pattern. The release profile of ceftazidime in the initial period up to 1 h and also in the second stage was fitted with Korsmeyer–Peppas kinetics, which was consistent with non-Fickian transport, influenced by diffusion and relaxation [norfloxacin/β-CD complex incorporated into a liposome using free multilamellar vesicles was prepared. NMR spectroscopy provided strong evidence of the incorporation of this complex into the liposomes [paromomycin, were developed for the treatment of visceral leishmaniasis. In vitro drug release followed a biphasic pattern, showing a sustained drug-release profile of up to 57% (amphotericin B) and 21.5% (paromomycin) within 72 h and an initial burst release  within 4 h as a result of the presence of the drug on the surface of the NPs. [Lipid-based nanocarriers can be used for targeted delivery, be administrated by a variety of routes, and even load both lipophilic and hydrophilic drugs . Three dlaxation . A ternaiposomes . Whereasthe NPs. . The autChitosan is a biocompatible and biodegradable polymer, widely used in NPs for drug delivery. Three methods of complex preparation were used to obtain a ternary system of florfenicol (FF) with HP-β-CD and chitosan NPs . In vitrlevofloxacin to the eye [Chitosan NPs based on SBE-β-CD were obtained by the ionotropic gelation method, for the delivery of  the eye . The in  the eye .metronidazole/β-CD and metronidazole/HP-β-CD ICs that have been embedded in chitosan NPs [Salmonella, and increased by 25% against S. aureus, by 9% against E. coli, and by 8% against Bacillus cereus, respectively [Similarly, ionic gelation methods have been used for osan NPs . Associaectively .levofloxacin/HP-β-CD complexes, the liquid/liquid co-precipitation method and the ionic gelation technique were used to formulate NPs consisting of chitosan in the range of 0.1–0.3% (positively charged) and tripolyphosphate in the range of 0.1–0.5% (negatively charged) as the cross-linking agents [For g agents . Complexciprofloxacin for the development of a sustained release system, as demonstrated during a 24 h study. Qβ-CD-g-CH-ciprofloxacin NPs showed a better inhibitory effect against E. coli and S. aureus than Qβ-CD-g-CH and chitosan alone. The authors postulated that the mechanism of antibacterial activity was related to the positive charge density of quaternised chitosan absorbed onto the negatively charged cell surface of bacteria, leading to leakage of protein components and other intercellular constituents.Dhiman and Bhatia  preparedlevofloxacin, were complexed with β-CD, and conjugated to NPs of curdlan  using epichlorohydrin [Mycobacterium smegmatis residing in macrophages within 4 h, thus achieving high therapeutic efficacy.Two anti-tuberculosis drugs, namely rifampicin and rohydrin , to achiMeropenem/γ-CD complex prepared by means of the liquid CO2 method was encapsulated into poly(lactic-co-glycolic acid) (PLGA) NPs by the double emulsion solvent evaporation method [S. aureus and P. aeruginosa), but was unable to improve drug permeability or reduce drug efflux rates in a Caco-2 cell monolayer model [Due to the enormous amounts of monomers available and the virtually unlimited ability to functionalise them, synthetic polymers have recently gained importance in the context of drug delivery. n method . The foler model .roxithromycin was encapsulated in the β-CD and HP-β-CD cavity also using solvent evaporation, and then each of the resulting complexes was separately loaded into PLGA to synthesise NPs [E. coli and S. aureus) in the following order: roxithromycin/PLGA > HP-β-CD/roxithromycin/PLGA > β-CD/roxithromycin/PLGA. The authors suggested that the difference in antimicrobial properties is mainly due to the formation of strong electrostatic interactions between the individual components of β-CD/roxithromycin/PLGA and HP-β-CD/roxithromycin/PLGA systems, which hinder the release of the drug from these formulations.Similarly, sise NPs . The desdoxycycline HCl, FF, and HP-β-CD as a host molecule, PVP as a polymeric carrier, and HPMC as a suspending agent, was prepared by saturated solution stirring combined with the high-pressure homogenisation method [Streptococcus suis, Actinobacillus pleuropneumoniae, and Haemophilus parasuis, as well as good physicochemical and pharmacokinetic properties. The suspension increased the bioavailability of doxycycline HCl and FF by 1.74- and 1.13-fold, respectively. The suspension increased the stability of doxycycline HCl in aqueous solution while prolonging the release of both compounds in phosphate-buffered saline (PBS) at pH 7.4. After 24 h, the cumulative release was greater than 90% for both drugs, with a burst release within 2 h.A microparticle suspension, which consisted of n method . The resmeropenem [Self-assembly CD-based NPs formed by CMC and a quaternary amino β-CD polymer (QA-β-CD) were prepared for the delivery of eropenem . It was eropenem .moxifloxacin by 20 times. The binding efficiency increased due to the multi-point interaction of the moxifloxacin molecule with the functional groups of the oligomeric carrier [In another work, NPs of SBE-β-CD oligomers were synthesised using 1,6-hexamethyl diisocyanate (HDI) as a bifunctional condensing agent, thus increasing the complexation efficiency of  carrier .E. coli were observed for the sample S5 (the most densely cross-linked of SBE-β-CD oligomers) with up to three-fold higher as compared to free moxifloxacin and the complex with monomer SBE-β-CD. Moreover, the sample S5 showed a tendency for prolonged action [Another paper demonstrated that cross-linking of derivatised CDs  with HDI allowed to obtain NPs with diameters of 100–200 nm with distinct binding properties, strongly depending on the nature of the CD substituent, degree of oligomerisation, and charge of the NP . Interesd action . Additiod action . In the amikacin sulphate to the lungs by encapsulation into β-CD (7.5% w/v) microspheres has been proposed to optimise the therapeutic efficacy and reduce the toxicity of this antibiotic [w/v) were synthesised and found to encapsulate amikacin. Zhao et al. [azithromycin with HP-β-CD and its polymer were prepared, which led to a 9- or 18-fold increase in solubility, respectively, compared to sole azithromycin.The idea of targeting tibiotic . The <5 o et al.  synthesiornidazole [E. coli and S. aureus confirmed the maintenance of the antibacterial activity of ornidazole.Polymer microspheres of β-CD were obtained by inverse emulsion polymerisation with epichlorohydrin as a cross-linking agent and loaded with nidazole . The relmetronidazole by adding an acetone amphiphilic CD solution to an aqueous solution of metronidazole with or without Pluronic PE/F68®®® as the surfactant [Another drug-delivery system was based on nanospheres made of hexanoyl-β-CD and rfactant . An opticefadroxil/β-CD-based nanosponges (NSs) with diphenylcarbonate for the cross-linking was developed to prevent hydrolysis of the lactone ring and prolong the drug release to achieve the desired serum level [A new approach of um level . XRPD, DNorfloxacin-loaded NSs were developed based on β-CD, using diphenyl carbonate as a cross-linking agent to improve the physicochemical properties of the drug [the drug . A 1:2 Camoxicillin, β-CD, and chitosan/sodium alginate/graphene oxide (GO) NPs has been prepared [A supramolecular nanocomposite consisting of prepared . GO was ampicillin, ceftriaxone, and other compounds  against multidrug-resistant bacteria by encapsulating the drugs into β-CD attached to NPs of zinc oxide (ZnO) to form the ZnO-CD-drug complex. The conjugates showed a decrease of MIC for different bacteria as well as minimal cytotoxicity to human cells.Akbar et al.  enhancedchloramphenicol in the IC [P. aeruginosa (the most sensitive to this system), E. faecalis, K. pneumoniae, and S. aureus.Computational studies were performed to predict that γ-CD is the preferred oligosaccharide that allows for the strongest interaction with n the IC . Consequtetracycline delivery for the treatment of periodontal disease were prepared using the electrospinning process: (i) polycaprolactone (PCL) loaded with tetracycline and (ii) PCL with tetracycline/β-CD complex [tetracycline/HP-β-CD ICs were mixed with water-soluble nontoxic biopolymer pullulan and, finally, NF networks were obtained via the electrospinning technique. The study demonstrated increased water solubility and a faster release profile of pullulan/tetracycline/HP-β-CD NFs  compared to the pullulan/tetracycline system (65% maximum release in 8–10 min). The release profile of pullulan/tetracycline/HP-β-CD NFs did not fit zero/first-order and Higuchi models, suggesting that tetracycline is not released in a time-dependent manner from the water-insoluble planar matrix. On the other hand, the relatively higher R2 in the Korsmeyer–Peppas model suggested that irregular/non-Fickian diffusion and erosion-controlled release of tetracycline from pullulan/tetracycline/HP-β-CD NFs was observed. In addition, the pullulan/tetracycline/HP-β-CD NFs readily disintegrated when wetted with artificial saliva, while the pullulan/tetracycline NFs were not completely absorbed in the same simulated environment. Pullulan/tetracycline/HP-β-CD NFs showed promising antibacterial activity against S. aureus and E. coli [Two nanofibre (NF) systems for  complex , and 93% E. coli .ciprofloxacin at room temperature or under the influence of sonic energy were incorporated into NFs via electrospinning based on PCL. The controlled release of ciprofloxacin from the PCL NFs at pH 7.2 was as follows: β-CD/ciprofloxacin (sonic energy) > α-CD/ciprofloxacin (sonic energy) > β-CD/ciprofloxacin (room temperature) > α-CD/ciprofloxacin (room temperature) > ciprofloxacin [ICs of α-CD and β-CD with floxacin . The relfloxacin . The IC floxacin . ComputaE. coli and S. aureus was much higher and more sustained, compared to the unmodified CFs.Another study reported a so-called “click reaction”, which was performed between mono-6-propargylamino-6-deoxy-β-CD and azidated cellulose fibres (CFs) to produce covalent grafting of β-CD with the included ciprofloxacin and CFs . The amoofloxacin in a 1:1 molar ratio with PEG (20% w/w) as a compatible solubilising agent, thus enhancing complex formation and water solubility [w/w) citric acid by the electrospinning method, to synthesise NFs of PVA/α-CD/ofloxacin/PEG. The release of ofloxacin from the PVA NFs was determined, with the results showing a stable release rate of ofloxacin from the NFs over 23 h. The antibacterial effect of NFs against E. coli and S. aureus was also investigated.An ultrasonic bath was used to prepare a ternary system consisting of α-CD and lubility . This reroxithromycin in respiratory tract infection. The role of HP-β-CD was to increase the solubility of the drug, while the incorporation of TPGS into PVA-based NF was to accelerate wetting, disintegration, the dissolution rate, and overcoming bacterial resistance. Moreover, TPGS may accelerate the dissolving speed of the NF mat and overcome the bacterial resistance by inhibiting efflux pumps. The released profiles of roxithromycin from NFs with and without TPGS in the pH 6.8 buffer mimicking the pH of artificial saliva fluid were 84% and 46%, respectively, at 10 min. The observed drug-release data suggested that more than 80% of the drug amount can be released from NFs with the TPGS mat in the oral cavity, which may lead to the fast absorption and initiation of pharmacological actions. The obtained NF showed a higher antibacterial potential in the disc-diffusion method against E. coli and S. aureus compared to other NF formulations. The antibacterial potential of the PVA/HP-β-CD/TPGS/roxithromycin NF mat was assessed in an in vivo test in a Streptococcuspneumoniae-infected mouse model. The authors concluded that the application of this NF to the oral cavity reduced the pneumonia-related disorders in the lung tissue.In a different approach, Kim et al.  used theGentamicin sulphate shows poor availability to target cells after oral administration. To overcome this obstacle, polyurethane (PU) fibrous membranes were developed with the addition of 15% w/w of β-CD, functionalised with nanochitosan (5% w/w) [(5% w/w) . The amimetronidazole in water was significantly improved by preparing NF webs of metronidazole ICs with HP-β-CD via electrospinning [Additionally, the solubility of spinning . These Ndoxycycline/HP-β-CD complex for the treatment of corneal neovascularisation (CNV) [2+ cations provided a synergetic protection of the unstable site of doxycycline at the N(CH3)2 moiety. Then, an artificial neural network was developed to predict the optimal conditions for the preparation of doxycycline/Mg2+/HP-β-CD complexes based on computational modelling [2+/doxycycline equal to 4 and 10.8, respectively, as well as an inclusion time of 12 h and temperature of 25 °C.Several studies have focused on the preparation of the on (CNV) ,107. Tetodelling . The higtetracycline HCl to the colon [A new composite hydrogel, namely maleated CD-grafted-silylated montmorillonite, has been developed for the specific delivery of he colon . MontmorBlanco-Fernandez et al.  preparedAnother polymer network was created with the use of sterculia gum, which is a complex, branched, and partially acetylated polysaccharide, consisting of glucuronic acid, galacturonic acid, and carbopol . The preGauzit Amiel et al.  preparedS. aureus, E. coli, and P. aeruginosa showed an improvement in the antimicrobial activity of ciprofloxacin in a supramolecular hydrogel [Recently, self-assembled supramolecular hydrogels based on polypseudorotaxane systems were prepared for delivery of ciprofloxacin to the eye, mixing a drug-loaded dispersion of poloxamer 407 with α-CD solution under continuous agitation . A signihydrogel .w/v) azithromycin, the equimolar amount of HP-β-CD, 18.91% (w/v) of poloxamer 407, and 0.35% (w/v) of Carbopol 934P [A new formulation was proposed for the temperature-sensitive in situ gel, consisting of 0.5% (pol 934P . This fovancomycin HCl (5.5 mg/mL), α-CD , and Pluronic F127 . Vancomycin HCl was incorporated to the formulations before Pluronic F127 and α-CD solutions were mixed. This drug was physically entrapped in the supramolecular gel and did not interfere in the Pluronic F127–α-CD interaction. Gel formulation without α-CD released 80% of the drug during the first 24 h, while that prepared with 9.7% α-CD released less than 45% in the same time period. In this last case, 100% release was achieved at day 7. Meanwhile, the Pluronic F127 concentration did not significantly affect the vancomycin release rate. The gels prepared with 6.5% copolymer and 5% or more α-CD were stable for at least two months when stored at 20 °C and showed activity against S. aureus.Simões et al.  obtainednovobiocin, and vancomycin. The release of vancomycin from these gels was slower than from dextrose gels, as dextrose is chemically similar to CD but incapable of forming a complex with a drug, leading the authors to the conclusion that CD ICs were formed. The release was faster with novobiocin and vancomycin than with rifampicin due to their higher solubility in release medium [New drug-delivery hydrogels based on the β-CD polymer with the addition of cross-linkers such as 2-isocyanatoethyl 2,6-diisocyanatohexanoate or diisocyanatohexane have been developed . The gele medium .Cefradine was combined with a medusa-like β-CD with 1-methyl-2-(2′-carboxyethyl) maleic anhydrides to improve drug delivery to specific targets, including weakly acidic tissues or organelles, such as tumours, inflammatory tissues, abscesses, or endosomes [doxycycline/α-CD complex loaded into a PLGA-based implant injectable in situ to reduce irritation and improve the stability of doxycycline in the aqueous medium [ndosomes . Interess medium . The resenrofloxacin and FF was prepared [S. aureus and E. coli), released enrofloxacin, and FF over a significantly extended period of time . The results indicated that the porous structure of γ-CD-MOF controls the release behaviour of both drugs. In addition, antibiotic-loaded γ-CD-MOF showed better long-lasting activity , nontoxicity, as well as excellent biocompatibility with mammalian cells and tissues both in vitro and in vivo.In another approach, a γ-CD metal-organic framework (MOF) loaded with prepared . The γ-CS. aureus and E. coli with 99% inhibitory efficiency for 50 h.Next, a β-CD covalent organic framework (COF) loaded with enrofloxacin was produced, obtained by blending the drug and COF into a solution, and incorporated into thermoplastic polyurethane fibres via electrospinning . The druciprofloxacin composite films were developed for use in medical coatings with antibacterial properties [S. aureus, Sarcina lutea, B. cereus, and B. subtilis, as well as Gram-negative bacteria E. coli and P. aeruginosa. Novel ternary polyurethanes simultaneously containing β-CD and β-glycerophosphate groups  cross-linked by HDI have been designed, using the properties of both polyalcohols: the inclusion capacity of β-CD toward hydrophobic drug molecules and the bioactivity of β-glycerophosphate [Polyurethane/β-CD/operties . The teshosphate . The resIn another approach, new macromolecules were synthesised in a reaction between ciprofloxacin and β- or γ-CD, using chloroacetyl chloride as a linking agent . The desGarcia-Fernandez et al.  developeA modern delivery system for ciprofloxacin was developed in combination with the HP-γ-CD polymer with the addition of citric acid as a cross-linking agent, grafted onto a woven polyethyleneterephtalate (PET) vascular prosthesis . The CD levofloxacin lactate. PAMAM dendrimers have well-defined structures that allow for precise control of the size, shape, and terminal group functionality, enabling potential pharmaceutical applications such as a drug-delivery vessel. This work is mainly concerned with understanding the host–guest supramolecular behaviour using NMR and IR spectroscopy. Another strategy is the development of polypropylene mesh devices, grafted in two steps with HDI and β-CD, and then loaded with levofloxacin HCl [Hunag and Kang  synthesiacin HCl . The antvancomycin was significantly better than that of the diffusion-only control polymers. The release of drug from dextran and CD-based polymers in PBS at pH 7.4 showed rapid, burst release for vancomycin-loaded dextran, while from CD polymers showed a reduced burst followed by a longer sustained release period, varying with the length of the cross-linker. The bactericidal activity of vancomycin-loaded CD polymers against S. aureus continuously showed a zone of inhibition up to 20 days, while the dextran polymers were only able to clear bacteria for 10 days. Next, a vancomycin-delivery nanosystem was developed based on supramolecular amphiphiles that can self-assemble into nanostructures [S. aureus and MRSA were 2- and 4-fold lower, respectively, compared to vancomycin alone.In another study, Thatiparti et al.  describeructures . A novelCeftiofur acid was described as a long-acting injection in patent CN103230364A [3230364A . The forchloramphenicol with SBE-β-CD, characterised with higher topical concentrations, due to increased solubility and reduced penetration through the cornea (demonstrated using a Franz diffusion cell system). The tear fluid elimination kinetics study showed that the chloramphenicol/SBE-β-CD eye drops significantly extended the residence time, increased the concentration of antibiotic in the conjunctival sac, and did not irritate the eyes of rabbits.Xu et al.  formulatciprofloxacin and HP-β-CD, in which the drug solubility tripled at pH 5.5 and doubled at pH 7.4. The complex was more stable at pH 5.5 than at pH 7.4, and the stability constant of the complex was increased by the addition of 0.1% (w/v) polymer (HPMC and/or PVP) to the aqueous medium. In a further study, ophthalmic in situ gelling systems containing ICs of ciprofloxacin hydrochloride with HP-β-CD at a 1:1 molar ratio were developed to reduce pre-corneal elimination and improve the bioavailability and therapeutic response [Bozkir et al.  developeresponse . As a reRufloxacin was used in combination with CDs and HPMC in the formulation of ophthalmic solutions [w/v) HPMC to solutions containing rufloxacin/HP-β-CD complexes increased the solubilising effect of this CD, thus reducing the amount of CD necessary for solubilisation of 0.3% (w/v) rufloxacin. Preliminary pharmacokinetic data in rabbits indicated that the ocular bioavailability of 0.3% (w/v) rufloxacin solubilised by HP-β-CD was higher than the 0.3% (w/v) rufloxacin suspension used as a reference.olutions . The addnorfoxacin/β-CD complexes and other excipients were developed and assessed before and after compression [®®® showed the highest dissolution rate when using crospovidone, achieving 98% drug release.In other studies, tablet formulations consisting of pression . The stuceftazidime and vancomycin in antibacterial formulation for the treatment of bacterial keratitis [Interestingly, HP-β-CD overcomes the incompatibility of the combination of eratitis . The forThis article provided an overview with a discussion of 212 literature reports on the delivery of antibiotics and antimicrobial agents’ inclusion in CDs. One third (70) of the cited articles discussed the impact of CD complexation on antibacterial activity; however, there are relatively few studies (10) on increasing the permeability through biological membranes.In the case of beta-lactams, the main goal of CD complexation was to improve the chemical stability (in 23 out of 61 papers), since the strained beta-lactam ring is prone to degradation reactions such as amide bond hydrolysis. The problem of chemical instability also concerns the tetracycline group (in 6 out of 14 reports), where the tertiary amine and methyl group are the labile fragments of the molecules, and application of CDs seems to be a promising remedy. The main reason for the preparation of chloramphenicol/CD complexes was the low water solubility (in 7 out of 12 articles) and the desire to reduce the toxicity of chloramphenicol. Another clinically significant advantage of the doxycycline/CD complexes is the increased effectiveness in combating bacterial biofilms. Meanwhile, the quinolones are the most studied group regarding CD complexation, with a total of 74 scientific papers mostly on the preparation of multi-component delivery systems. On the other hand, the inclusion of macrolides (16 reports), aminoglycosides (3 reports), and glycopeptides (9 reports), which are compounds with large molecules, into the CD cavity is less likely. However, contradictory statements appear in various articles, i.e., some authors state that inclusion does takes place and others that it does not. Therefore, further research is needed, especially in the field of antibacterial macromolecules, to determine the possible geometry of the combinations and to pinpoint the interactions that hold the drug and CD together.To obtain a controlled and sustained release of the loaded antibiotic and prolonged systemic circulation, more sophisticated drug-delivery systems were developed, including nanoparticles, microparticles, liposomes, nanosponges, nanofibres, hydrogels, and macromolecules.Sustained release and targeted release are important directions for the development of a next generation of personalised therapies, providing powerful means of safe antibiotic therapy, offering an opportunity to reduce antibiotic resistance. Targeted drug release has grown in importance as medicine moves towards precision therapy. Such a delivery system crosses biological barriers to reach the target organ, tissue, or cell prior to drug release. In this way, the bioavailability is improved, and the damage caused by binding to the inappropriate sites is reduced. An example can be both doxycycline and tetracycline directed against colon diseases, which were designed in such a way that the release of the drug from the nanosystem takes place at a certain pH value in the gastrointestinal tract, which is an unquestionable advantage for safe pharmacotherapy.Thus, the interest in CDs is growing steadily and this trend will continue in the coming years due to their versatility and fascinating ability to improve pharmaceutical formulations in the design of innovative therapies. This article differs from many other reviews in that it describes the current state-of-the-art from the perspective of individual drugs, thus showing where much research has been carried out so far and pointing to new lines of research in the field of antibacterial drugs.


The purpose of this work was to develop, characterize and test new low-cost materials suitable for removing methylene blue dye from water and wastewater by adsorption. The solid materials consisted of silica gel powder (SG), silica gel mixed with eggshell powder (SG-ES) and a mixture of silica gel with sand from the western Iraqi desert (SG-SI). The samples were milled by using an electrical mixer and a ball mill, followed by a drying step. In addition, desert sand was acid-treated in order to remove impurities. The structure and chemical composition of the samples were investigated by X-ray diffraction (XRD), a scanning electron microscopy technique equipped with an energy-dispersive X-ray spectrometer (SEM-EDX), a low-temperature nitrogen adsorption (BET) technique, thermo-analytical (TG/TGA) measurements and Fourier-transformed infrared spectroscopy (FTIR). The previously mentioned materials were tested to remove methylene blue from an aqueous solution. The adsorption experiments were monitored by ultraviolet–visible (UV-Vis) spectrophotometry and showed that SG and SG-ES gave promising results for the methylene blue removal from water. After 40 min of treatment of the aqueous solution containing 10 mg/L of MB at room temperature, the tested SG, SG-ES and SG-SI materials were found to have 86%, 80% and 57% dye adsorption efficiency, respectively. Taking into consideration not only the adsorption activity of the studied material but their availability, cost and concepts of cleaner production and waste minimization, the developed silica gel with eggshell can be considered as a good, cost-effective alternative to commercially available activated-carbon-based adsorbents. Different kinetic and isotherm models were fitted to the experimental results. A pseudo-second-kinetics-order model revealed high correlation fitting, while the Freundlich model was found to appropriately describe the adsorption isotherm. The thermal stability during the possible regeneration process of the SG-ES adsorbent mixture and its interaction mechanism with cationic dye was discussed. Fo. Fo45]. EDX results were recorded to determine the compositions of the studied samples . The ana2 (97–99%), and minor amounts of Al2O3 (0.75–2.5%) were detected. Possible other natural sand impurities, such as K2O, Fe2O3 and CaO were illuminated by acidic treatment and were not detected by EDX or XRD. The result is in agreement with an earlier reported study [2O impurities in small amounts. The major oxides in the eggshell were CaCO3 (99%), accompanied by some SO3, MgO and SiO2 (amounts of less than 1 wt%). The major component of chicken eggshell is calcium in the form of calcite; however, minor inorganic elements, such as boron, chromium, copper, iron, iodine, manganese, sulphur, selenium, silicon, and zinc are expected to be present in the structure [The main component for treated Iraq sand and silica gel is SiOed study . Both satructure . The composition of the mixed SG-EG sample estimated by EDX analysis was 1:1.6. The measured ratio was higher than the theoretical values used for preparation (1:1 mass ratio).The FTIR-ATR spectra of SG, ES and SI and the prepared adsorbents SG-ES and SG-SI are displayed in −1, where the stretching bands of water (νHOH) are expected, as well as by the deformation band of the adsorbed water (δHOH) at 1631 cm−1. Although the stretching bands of hydroxylated silica (νSi-OH) groups were not observed [−1 could be assigned to the deformation of Si-OH hydrogen bonded with water molecules, as reported in [−1 (deformation), 795 cm−1 and 1060 cm−1 (stretching), with the latter having a shoulder around 1149 cm−1 [In harmony with the XRD results , the majobserved ,49, the orted in . The int149 cm−1 .−1, 1076 cm−1, 1055 cm−1, 777 cm−1 and 694 cm−1, originating from Si-O-Si stretching, while the bands at 694 cm−1 and 514 cm−1 were assigned to Si-O-Si deformations [The SI spectrum can be similarly interpreted as SG; however, the presence of ordered, crystalline quartz in the SI sample , XRD resrmations . Overallrmations ,53.−1 is due to the anti-symmetric stretching, while bending vibrations were observed at 872 cm−1 (out-of-plane) and 711 cm−1 (in-plane) [3 [−1 suggests the presence of a small amount of aragonite-CaCO3. The low intensity band at 1795 cm−1 could be assigned to a combination band of the carbonate ion [In harmony with the XRD results , the eggn-plane) ,54. Thislane) [3 , while tThe infrared spectra of the physically mixed adsorbents (SG-ES and SG-SI) can be regarded as the superimposition of the individual constituents  and are BET) and micropore (Smicro) surface areas, total volume (V) for microspores of sizes between 1.7 and 100 nm and micropore volume (Vmicro) for pore sizes less than 2 nm. The pore size distribution and the average pore diameter (Dav) could also be calculated. The information delivered by nitrogen adsorption analysis is displayed in The detailed porous structure of an adsorbent is a key factor in both the adsorption’s overall performance and the diffusion role in the adsorption equilibrium settlement. The most convenient method for exploring the porous structure is the pure nitrogen adsorption performed at −196 °C, known also as BET adsorption. The adsorption data processed by applying BET an BHJ models can deliver various information, including total (S2/g depending on the place of origin [2/g) was close to the value of 3.2 m2/g reported for quartz sand from Russia [The surface area of the natural sand various from 1.8 to 15.0 mf origin ,57. The m Russia . 2/g). Generally, commercially available silica gels used for drying and adsorbing moisture are porous materials with a large surface area of about 400–800 m2/g [The SG desiccant sample has the largest surface area among the investigated samples (633 m800 m2/g . 2/g), while SI and ES have surfaces of two orders of magnitude lower . There are significant differences between the morphological characteristics of the initial materials, as well as between the prepared mixtures. The SG has a relatively high specific surface area , recommending the use of the solids for the adsorption test. SG-ES has a higher surface area than the SG-SI mixture. This could be because the microporous structure is better preserved in the case of SG-SE, where the Vmicro value for SG-ES is higher than for the SG-SI sample  and eggshell (35.5 nm) are higher than for silica gel (2.3 nm) and the mixed samples (2.8–3.1 nm). The pores defined between the mixed particles are rather narrow, with a silica gel origin. The high values of the specific surfaces areas of the mixed samples and the narrow pores are a preamble for the good adsorption potential of the methylene blue molecule, which is well accommodated in the available pore space. According the literature data, the length of a methylene blue molecule is around 1.45 nm , and thedihydroxylation of the silica surface [The thermo-analytical investigations results are presented in  surface ,62. The  surface . SI shows only minor mass loss upon heating to 1000 °C (∑Δm = −0.8%) B. The fi3 , with the rest being the organic matrix and various trace elements [2 , indicating the low amount of surface adsorbed water C. Poultrelements ,69. Aparelements ,71, and  CO2 see . The CaCterature ,72.3 content. The carbonate content of the dry sample was estimated to be 48.90% (see Since the two adsorbent mixture (SG-SI and SG-ES) samples are physical mixtures, their thermograms can be regarded as an averaged superposition of the individual constituents D,E. In t.90% see . Conside.90% see . This va.90% see  analysis.90% see .An MB adsorption study was carried out on SG and the SG-SI and SG-EG composites. The contact time between the solution and the sorbents varied between 0 and 80 min . For the preliminary tests, the initial MB concentration was 10 mg/L, the solution volume was 40 mL and the adsorbent dose was 10 mg (corresponding to 0.25 g/L). The experiments were run at room temperature.+ ions on the solid surface of the adsorbent and, hence, the removal of MB is lower. It was observed that with increasing pH from 3.2 to 8 increases the negative charge density on the surface and results in an enhancement in the cationic MB [The adsorption of ionic dyes depends on the pH of the solution to be treated. The pH solution was set to 7 since at a pH close to the neutral region the optimum uptake of pollutant was expected . In a moionic MB . The MB adsorption results are shown for silica gel and silica-gel-based samples. The results displayed in The adsorption capacities of the three samples were calculated in mg of dye per g adsorbent and followed the trend: SG (34.3 mg/g) > SG-SE (32.0 mg/g) > SG-SI (22.8 mg/g). −1 in the FT-IR spectrum , is high, at about EUR 655 per 1 kg. The cost of SiO2 desiccant and sand (50–70 mesh) on the price list of the Sigma Aldrich chemical distribution company in Europe is about EUR 47 and EUR 65 per kg, respectively [The MB adsorption capacity results achieved in this work show that the performance/adsorption activity of our composites is moderate in comparison with the literature data . Table 3245 mg/g ), which ectively . TherefoIt can be seen from the already studied systems listed in Since the SG-EG sample has shown good adsorption properties towards MB removal and could be considered as a cheaper adsorbent compared with silica gel for the treatment of dye-contaminated wastewater, kinetic studies were performed for the data collected using this sample. Different kinetic models can be used to analyse the experimental adsorption data from the solutions . In this2 = 0.999 for second order, R2 = 0.843 for first order). The better fit of the pseudo-second-order model in a similar adsorbate–adsorbent system had also been reported earlier [e cal for SG-EG was slightly higher compared with the experimental value obtained. The qt against t1/2 plot corresponding to the Weber–Morris model (Equation (5)) reveals a poor fit; moreover, the curve does not pass through the origin. Therefore, intra-particle diffusion is not the rate-controlling step. The I value is an indication of the occurrence of the boundary layer effect during sorption. The larger the intercept, the greater the contribution of the surface sorption in the rate-controlling step [The superiority of the pseudo-second-order model over the pseudo-first-order version results from its excellent correlation coefficient ) and log qe versus log Ce (Equation (7)), respectively, displayed in 2) of 0.9949  followed by drying at 60 °C. In the literature, six adsorption–regeneration processes were studied, showing an 18% reduction in sample capacity towards MB adsorption .The regeneration of silica gel is usually performed at relatively at low temperatures between 90 and 150 °C . At thisThe thermo-analytical investigation result for SG-ES E support2 contents: 99.2% and 97.5%, respectively. Furthermore, the ES sample’s most abundant component was calcium carbonate . Within this work, the adsorption of MB from water using prepared different low-cost and available materials, such as silica gel (SG) from desiccant packets, sand from Iraq (SI), eggshell (ES) and their mixtures, was studied. The prepared sorbents were successfully prepared and characterized. The EDX analysis showed that SG and SI have high SiO2/g, respectively). SI and ES alone were not suitable adsorbent materials for waste treatment due to the low values of their surface area . The values of the specific surface area and free-pore volume had an outmost effect on the adsorbent material effectiveness in the adsorption efficiency. It was noted that with a decrease in surface area and pore volume values, the adsorption efficiency of silica based adsorbents diminished: 86% SG (SBET = 633 m2/g) < 80% SG-ES (SBET = 360 m2/g) < 57 %SG-SI (SBET = 330 m2/g)The low-temperature nitrogen adsorption BET analysis revealed that the porosity and specific surface areas of the mixtures SG-SI and SG-EG increased by a significant extent compared with the sand and eggshell single-component measurements . The RE value of 86% for pure silica gel does not bring a significant economic benefit, since at around 50% weight, the eggshell allows the use of an easily available and cheaper adsorbent price. Therefore, the silica gel–eggshell mixture is recommended as a possible adsorbent for the removal of cationic dye from wastewater. The best behaviour among the mixed samples was noticed for SG-EG. In this system, the MB 10 mg/L removal from aqueous solutions reached the equilibrium within 40 min. The SG-ES mixture produced the highest dye removal yields per mass unit (RE = 80%; qAccording to our kinetic studies, we concluded that the MB adsorption results for water on SG-ES excellently fitted the pseudo-second-order adsorption model. The data fitting to the Langmuir and Freundlich isotherms indicated that the Freundlich model fitted the data well, allowing us to conclude that the adsorption does not occur in the monolayer and is not a homogenous process.It is proposed that the hydrogen bonding and electrostatic interaction occurred between the SG-EG adsorbent surface and cationic MB molecules during the treatment process. Based on TG analysis, the newly prepared SG-EG adsorbents are stable up to 200 °C; therefore, a regeneration temperature under 200 °C is recommended.